The central theme of this Program Project is directed toward elucidating mechanisms underlying the response of the lung to elastase injury-a situation clinically relevant to the development of COPD. Our hypotheses is that elastase-induced degradation of lung tissue results in a change in the viability of elastogenic cells and their phenotypic dependent on the proximity to and duration of elastase injury and exposure to matrix-released growth factors and secreted cytokines. Normally these processes result in localized repair of elastin without inducing a general fibrotic response. However, the loss of elastin combined with release of matrix bound growth factors and cytokines can lead to chronic release or elastase resulting in inefficient elastin repair and subsequent destruction of tissue integrity. This renewal application builds on the accomplishments of the last funding period and proposes to expand our hypotheses to gain new insights into mechanisms underlying the response of lung to elastase injury. To pursue investigation of this central theme four Projects will address the overall hypothesis from common conceptual objectives with different experimental designs. Al four projects propose an integrated approach that combines in vitro culturing of pulmonary cells to understand mechanisms and in vivo animal model to test and further understand these mechanisms. The aims and experimental design of each project are intertwined to allow maximum interchanges of expertise and technical assistance. Dr. Foster will investigate the factors responsible for transcriptional up-regulation of the elastin gene in situations related to elastase injury. Dr. Nugent will investigate the role of proteoglycans in modulating the release and receptor binding of matrix bound growth factors. Dr. Pancenko will study the role of EGF receptor signaling in elastase-induced injury. Dr. Goldstein will study the effects of the cytokines, tumor necrosis factor- and interleukin 1beta, on elastin gene transcription and cell apoptosis. The four Projects will be supported by a Core facility that will provide central administrative services, cell cultures, microscopic analyses, and the implementation analyses, and the implementation and assessment of common animal experiments. Together, over the requested five years, we hope to contribute to the understanding of the mechanisms that underlie t he pathological events leading to the clinical manifestations of emphysema.